# Ligand‐Induced Electronic Response Enables Predictive QM/MM Simulations

## TL;DR

A new protocol improves QM/MM simulations by defining quantum regions based on electronic changes caused by ligands, enabling accurate and efficient modeling of complex systems.

## Contribution

The protocol objectively defines QM regions using ligand-induced electronic effects, enhancing predictability and transferability of QM/MM simulations.

## Key findings

- The method achieves chemical accuracy in binding energy predictions within ∼1–2 kcal/mol.
- It reduces computational cost at the DFTB level while maintaining accuracy.
- Validated across zeolite–guest and enzyme–inhibitor systems, showing cross-domain applicability.

## Abstract

Predictive modeling of large molecular systems demands methods that combine quantum accuracy with scalability. Although hybrid quantum mechanics/molecular mechanics (QM/MM) simulations offer such a framework, their predictive power has been limited by the subjective and system‐specific definition of the QM region. Here, we present an electronically informed protocol that objectively defines QM regions from ligand‐induced orbital shifts and charge‐redistribution, extracted in a single semiempirical fragment molecular orbital (FMO) calculation. Validated on both zeolite–guest and enzyme–inhibitor complexes, the method achieves chemical accuracy (within ∼1–2 kcal/mol on binding energies) while substantially reducing computational cost at the DFTB level. This cross‐domain strategy reframes QM/MM as a transferable design principle, bridging solid‐state catalysis and quantum biochemistry, and thereby providing a practical platform for predictive molecular engineering across diverse disciplines.

Quantum mechanics/molecular mechanics (QM/MM) simulations are powerful tools for modeling complex molecular systems; however, their predictability has been constrained by the ambiguous definition of the QM region. An electronically informed protocol is introduced that defines QM regions by quantifying guest‐induced orbital shifts and charge‐redistribution, providing transferable and interpretable boundaries across both materials and biological systems.